Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.1516G>C (p.Val506Leu)

CA404086496

926176 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 66c458e1-9a5e-40d0-a1cc-50db04bc5207
Approved on: 2024-02-23
Published on: 2024-09-25

HGVS expressions

NM_000527.5:c.1516G>C
NM_000527.5(LDLR):c.1516G>C (p.Val506Leu)
NC_000019.10:g.11113692G>C
CM000681.2:g.11113692G>C
NC_000019.9:g.11224368G>C
CM000681.1:g.11224368G>C
NC_000019.8:g.11085368G>C
NG_009060.1:g.29312G>C
ENST00000252444.10:c.1774G>C
ENST00000559340.2:c.1516G>C
ENST00000560467.2:c.1396G>C
ENST00000558518.6:c.1516G>C
ENST00000252444.9:c.1770G>C
ENST00000455727.6:c.1012G>C
ENST00000535915.5:c.1393G>C
ENST00000545707.5:c.1135G>C
ENST00000557933.5:c.1516G>C
ENST00000558013.5:c.1516G>C
ENST00000558518.5:c.1516G>C
ENST00000559340.1:c.237G>C
NM_000527.4:c.1516G>C
NM_001195798.1:c.1516G>C
NM_001195799.1:c.1393G>C
NM_001195800.1:c.1012G>C
NM_001195803.1:c.1135G>C
NM_001195798.2:c.1516G>C
NM_001195799.2:c.1393G>C
NM_001195800.2:c.1012G>C
NM_001195803.2:c.1135G>C
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Uncertain Significance

Met criteria codes 2
BP4 PM2
Not Met criteria codes 20
BP2 BP3 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PM6 PVS1 PM3 PM1 PM4 PM5 BA1 BS2 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1516G>C (p.Val506Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). BP4: REVEL= 0.296. It is below 0.5, so splicing evaluation is required. A) not on limits. B) does not create AG or GT. C) There is an AG nearby. Wt score: 6.76, Wt cryptic score: -25.36, Var cryptic score: -24.4. Var cryptic score/Wt cryptic score: 0.96. Var cryptic score/Wt score: -3.6. Variant is not predicted to alter splicing.
Met criteria codes
BP4
REVEL= 0.296. It is below 0.5, splicing evaluation required. A) not on limits B) does not create AG or GT C) There is an AG nearby Wt score: 6.76, Wt cryptic score: -25.36, var cryptic score: -24.4 var cryptic/wt cryptic: 0.96 var cryptic/wt score: -3.6 Variant is not predicted to alter splicing. So, BP4 is met.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met
Not Met criteria codes
BP2
No data available
BP3
No in-frame deletions/insertions
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No data available
PS3
No data available
PS1
No other missense variant with the same amino acid change
PP4
No data available
PP1
No data available
PP3
REVEL= 0.296. IT is not above 0.75, splicing evaluation required. A) not on limits B) does not create AG or GT C) There is an AG nearby Wt score: 6.76, Wt cryptic score: -25.36, var cryptic score: -24.4 var cryptic/wt cryptic: 0.96 var cryptic/wt score: -3.6 Variant is not predicted to alter splicing.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
Not a null variant (nonsense, frameshift, canonical +/- 1 or 2 splice sites, initiation codon, single or multiexon deletion)
PM3
No data available
PM1
Not in exon 4. Not a cysteine residue.
PM4
No in-frame deletions/insertions
PM5
1 other missense variants in the same codon: - NM_000527.5(LDLR):c.1516G>A (p.Val506Met) (ClinVar ID 251881) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
BS2
No data available
BS4
No data available
BS3
No data available
BS1
This variant is absent from gnomAD (gnomAD v2.1.1).
Curation History
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